Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency.

PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-γ and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-γ have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST). METHODS: We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings. RESULTS: The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Guérin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient's cells, the mutant IFN-γ was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-γ1b plus two antimycobacterial drugs. Treatment with IFN-γ1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-γ. CONCLUSION: We describe a patient with a new form of autosomal recessive IFN-γ deficiency, with intracellular, but not extracellular IFN-γ. IFN-γ1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-γ deficiency or at least an option to better control mycobacterial infection prior to HCST.

Life-threatening infections in human newborns: Reconciling age-specific vulnerability and interindividual variability.

In humans, the interindividual variability of clinical outcome following exposure to a microorganism is immense, ranging from silent infection to life-threatening disease. Age-specific immune responses partially account for the high incidence of infection during the first 28 days of life and the related high mortality at population level. However, the occurrence of life-threatening disease in individual newborns remains unexplained. By contrast, inborn errors of immunity and their immune phenocopies are increasingly being discovered in children and adults with life-threatening viral, bacterial, mycobacterial and fungal infections. There is a need for convergence between the fields of neonatal immunology, with its in-depth population-wide characterization of newborn-specific immune responses, and clinical immunology, with its investigations of infections in patients at the cellular and molecular levels, to facilitate identification of the mechanisms of susceptibility to infection in individual newborns and the design of novel preventive and therapeutic strategies.

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

COVID-19 associated severe mucocutaneous blistering eruptions: A case series.

Mucocutaneous eruptions are associated with numerous infectious processes and can present as erythema multiforme (EM), reactive infectious mucocutaneous eruption (RIME), Stevens Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN). Limited reports have detailed the association of these eruptions with SARS-CoV-2 infection. We present a series of eight cases of severe mucocutaneous blistering eruptions associated with SARS-CoV-2 infection. A retrospective case series was performed at six tertiary medical centers from March 1, 2020 to August 1, 2022. Inclusion criteria were met with a clinical diagnosis of EM, RIME, SJS, or TEN and a positive SARS-CoV-2 test (rapid antigen or polymerase chain reaction) less than 4 weeks prior to onset of dermatologic manifestation. Data was collected at time of each patient encounter. Eight patients met criteria with six pediatric patients (<18 years of age) having a median age of 15 years and two adult patients (>18 years of age) having a median age of 36 years. Patients were found to have a clinical diagnosis of RIME in 85.7% of cases. Oral mucosal involvement was the most common clinical finding (100%), followed by ocular (50.0%), urogenital (50.0%), and skin (37.5%) involvement. Evaluation did not reveal any additional infectious triggers in four patients. Evidence of possible concurrent or previous infectious triggers were identified in four patients. This case series highlights the development of severe mucocutaneous eruptions in association with COVID-19 infection, as well as the potential contributing role of concurrent or prior infections.

Fulminant echovirus 11 hepatitis in male non-identical twins in northern Italy, April 2023.

Echovirus 11 (E11) has recently been associated with a series of nine neonatal cases of severe hepatitis in France. Here, we present severe hepatitis caused by E11 in a pair of twins. In one of the neonates, the clinical picture evolved to fulminant hepatitis. The E11 genome showed 99% nucleotide identity with E11 strains reported in the cases in France. Rapid genome characterisation using next generation sequencing is essential to identify new and more pathogenetic variants.

How to: Diagnose inborn errors of intrinsic and innate immunity to viral, bacterial, mycobacterial, and fungal infections.

BACKGROUND: Inborn errors of intrinsic and innate immunity constitute the focus of a growing research field that investigates the molecular mechanisms underlying susceptibility to infections previously not considered part of the spectrum of inborn errors of immunity. These so-called nonconventional inborn errors of immunity often occur as infections caused by a narrow spectrum of microorganisms in otherwise healthy subjects. OBJECTIVES: This review aimed to provide a framework for identifying and evaluating patients with viral, bacterial, mycobacterial, and fungal infection needing further assessment for inborn errors of intrinsic and innate immunity. SOURCES: A literature search was performed using PubMed, from inception until 1 May 2022. The search included the following keywords: "inborn errors of immunity"; "inborn errors of innate immunity"; "primary immune deficiency"; "primary immunodeficiency"; "infections"; "infectious susceptibility"; "virus"; "pyogenic bacteria"; "mycobacteria"; "fungi". All article types were considered. CONTENT: We review the definition of what can be considered an inborn error of immunity and how the definition changed over the last ∼25 years. We further provide criteria to rule out secondary immunodeficiencies, identify patients needing further clinical and laboratory immunological assessment, and suspect and diagnose an inborn error of intrinsic and innate immunity. These steps are proposed as part of an algorithm. IMPLICATIONS: Patients with unexplained life-threatening infections, including otherwise healthy subjects, should be systematically screened for known inborn errors of immunity. The early diagnosis can prevent recurrence of life-threatening infections in the patients and reduce the total burden of infectious diseases.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-ß. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum.

PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation of tRNA pseudouridine, which plays a critical role in tRNA structure, function, and stability. Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature. We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia. This patient further expands the phenotypic spectrum of PUS3-related disorders to include a more severe syndromic presentation.

Neonatal Manifestations of Chronic Granulomatous Disease: MAS/HLH and Necrotizing Pneumonia as Unusual Phenotypes and Review of the Literature.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI), characterized by a deficient phagocyte killing due to the inability of NADPH oxidase to produce reactive oxygen species in the phagosome. Patients with CGD suffer from severe and recurrent infections and chronic inflammatory disorders. Onset of CGD has been rarely reported in neonates and only as single case reports or small case series. We report here the cases of three newborns from two different kindreds, presenting with novel infectious and inflammatory phenotypes associated with CGD. A girl with CYBA deficiency presented with necrotizing pneumonia, requiring a prolonged antibiotic treatment and resulting in fibrotic pulmonary changes. From the second kindred, the first of two brothers developed a fatal Burkholderia multivorans sepsis and died at 24 days of life. His younger brother had a diagnosis of CYBB deficiency and presented with Macrophage Activation Syndrome/Hemophagocytic Lympho-Histiocytosis (MAS/HLH) without any infection, that could be controlled with steroids. We further report the findings of a review of the literature and show that the spectrum of microorganisms causing infections in neonates with CGD is similar to that of older patients, but the clinical manifestations are more diverse, especially those related to the inflammatory syndromes. Our findings extend the spectrum of the clinical presentation of CGD to include unusual neonatal phenotypes. The recognition of the very early, potentially life-threatening manifestations of CGD is crucial for a prompt diagnosis, improvement of survival and reduction of the risk of long-term sequelae.

In vitro affinity for nicotine of soft contact lenses of different materials.

Smoking is a risk factor for the development of microbial keratitis and corneal infiltrates in contact lens (CL) wearers. It is still unknown if this risk is directly associated with the presence of nicotine in the eye and if adherence of nicotine on the CL can enhance these effects. A better understanding of the interaction between nicotine and CL materials could offer insights to explain this risk associated with smoking. The aim of this work was to compare the affinity of nicotine to different soft CL materials. CLs from FDA groups I, II, IV, and V were incubated in a 2-mM nicotine solution for 24 h and then in a 0.9% saline solution for the next 24 h. The amount of absorbed and released nicotine per CL was deduced as a function of time (t) by ultraviolet (UV) spectrophotometry and normalised to the mass of the hydrated CL. The data were described by the equation y = b -a t-1, where a and b are constants, and b represents the mass reached at the plateau after ~ 10 min of exposure. Groups IV and V displayed the highest (0.80 ± 0.09 µg) and lowest (0.27 ± 0.08 µg) nicotine absorption per mg of hydrated CL, respectively. The CL affinity for nicotine could be ascribed to the interaction between the positive charge of nicotine pyrrolidine nitrogen and the negative charges of the CLs, especially for the ionic IV group.

Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects.

Background: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with autism spectrum disorder (ASD). However, no real-world data are available on this population. Methods: We compared the period prevalence (March-May 2020) and symptom presentation of COVID-19 infections between a sample of individuals with severe ASD (n = 36) and the staff personnel (n = 35) of two specialized centers. Anti-SARS-Cov-2 antibody positivity was used as a proxy of infection. Additionally, we evaluated vaccine side effects in the same groups. Results: No significant difference was found between the prevalence of COVID-19 positivity between autistic participants and staff personnel. Levels of antibodies against the spike protein and the receptor binding domain were not significantly different between autistic and staff participants. The level of antibodies against the N-terminal domain were higher in autistic individuals. There was a significant difference between the prevalence of symptomatic COVID-19 in autistic participants (9.1%) compared to staff personnel (92.3%). The most frequent side effect among autistic participants was light fever. Conclusions: The present study provides preliminary data on COVID-19 transmission and presentation in ASD. Our data do not support the hypothesis of a higher susceptibility and severity of COVID-19 in people with ASD.

Immunological lessons from genome-wide association studies of infections.

Over the past few years, genome-wide association studies (GWAS) have been increasingly applied to identify host genetic factors influencing clinical and laboratory traits related to immunity and infection, and to understand the interplay between the host and the microbial genomes. By screening large cohorts of individuals suffering from various infectious diseases, GWAS explored resistance against infection, natural history of the disease, development of life-threatening clinical signs, and innate and adaptive immune responses. These efforts provided fundamental insight on the role of major genes in the interindividual variability in the response to infection and on the mechanisms of the immune response against human pathogens both at the individual and population levels.

Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection.

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in MEFV, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.

Phamacological treatment of persistant lower urinary tract symptoms after a transurethral resection of the prostate is predictive of a new surgical treatment: 10 years follow-up study.

AIM: To evaluate possible risk factors of re intervention in patients with benign prostatic enlargement (BPE) undergoing transurethral resection of the prostate (TURP). MATERIALS AND METHODS: A consecutive series of patients with LUTS and BPE underwent TURP in our center in 2004 and 2005 and they were then followed up to September 2016. Patients were assessed at baseline, 3-, 6-month postoperatively and yearly thereafter with medical history, international prostate symptom score, prostate specific antigen, maximal urinary flow rate, post void residual urine. Reoperation was defined as the requirement of a new TURP to relieve bothersome LUTS. Cox regression was used to determine covariates associated with reoperation rate and the Kaplan-Meier curve assessed the time to reoperation. RESULTS: Overall, 92 patients were enrolled. Median follow up was 142 months. 13 patients underwent a second TURP during the follow-up period (reoperation rate was 14%); out of them 9/13 (69%) received medical treatment for persistent LUTS (p = .001). The need of LUTS/BPE pharmacological treatment after TURP is an independent risk factor for a second surgical procedure (odds ratio 9,3; p = .001). Out of the 13 patients treated with a re-TURP, 12 (92%) underwent surgery within 5 years of follow-up. CONCLUSION: In our single center study, the need of LUTS/BPE pharmacological treatment was a predictive factor of a re-TURP. Considering that more than 90% of re-TURP were performed during the first 5 years of follow-up, it is assumable that a follow-up longer than 5 years is not needed in these patients.